Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Role of Helix 8 in Dopamine Receptor Signaling

  • Yang, Han-Sol (School of Pharmacy, Sungkyunkwan University) ;
  • Sun, Ningning (Department of Pharmacology, College of Pharmacy, Chonnam National University) ;
  • Zhao, Xiaodi (School of Pharmacy, Sungkyunkwan University) ;
  • Kim, Hee Ryung (School of Pharmacy, Sungkyunkwan University) ;
  • Park, Hyun-Ju (School of Pharmacy, Sungkyunkwan University) ;
  • Kim, Kyeong-Man (Department of Pharmacology, College of Pharmacy, Chonnam National University) ;
  • Chung, Ka Young (School of Pharmacy, Sungkyunkwan University)
  • Received : 2019.02.10
  • Accepted : 2019.03.22
  • Published : 2019.11.01
Download PDF
⟨ Previous Next ⟩

Abstract

G protein-coupled receptors (GPCRs) are membrane receptors whose agonist-induced dynamic conformational changes trigger heterotrimeric G protein activation, followed by GRK-mediated phosphorylation and arrestin-mediated desensitization. Cytosolic regions of GPCRs have been studied extensively because they are direct contact sites with G proteins, GRKs, and arrestins. Among various cytosolic regions, the role of helix 8 is least understood, although a few studies have suggested that it is involved in G protein activation, receptor localization, and/or internalization. In the present study, we investigated the role of helix 8 in dopamine receptor signaling focusing on dopamine D1 receptor (D1R) and dopamine D2 receptor (D2R). D1R couples exclusively to Gs, whereas D2R couples exclusively to Gi. Bioinformatic analysis implied that the sequences of helix 8 may affect GPCR-G protein coupling selectivity; therefore, we evaluated if swapping helix 8 between D1R and D2R changed G protein selectivity. Our results suggest that helix 8 is not involved in D1R-Gs or D2R-Gi coupling selectivity. Instead, we observed that D1R with D2R helix 8 or D1R with an increased number of hydrophobic residues in helix 8 relative to wild-type showed diminished ${\beta}$-arrestin-mediated desensitization, resulting in increased Gs signaling.

Keywords

References

  1. Ahn, K. H., Nishiyama, A., Mierke, D. F. and Kendall, D. A. (2010) Hydrophobic residues in helix 8 of cannabinoid receptor 1 are critical for structural and functional properties. Biochemistry 49, 502-511. https://doi.org/10.1021/bi901619r
  2. Beaulieu, J. M. and Gainetdinov, R. R. (2011) The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol. Rev. 63, 182-217. https://doi.org/10.1124/pr.110.002642
  3. Edward Zhou, X., Melcher, K. and Eric Xu, H. (2019) Structural biology of G protein-coupled receptor signaling complexes. Protein Sci. 28, 487-501.
  4. Faussner, A., Bauer, A., Kalatskaya, I., Schussler, S., Seidl, C., Proud, D. and Jochum, M. (2005) The role of helix 8 and of the cytosolic C-termini in the internalization and signal transduction of B(1) and B(2) bradykinin receptors. FEBS J. 272, 129-140. https://doi.org/10.1111/j.1432-1033.2004.04390.x
  5. Feierler, J., Wirth, M., Welte, B., Schussler, S., Jochum, M. and Faussner, A. (2011) Helix 8 plays a crucial role in bradykinin B(2) receptor trafficking and signaling. J. Biol. Chem. 286, 43282-43293. https://doi.org/10.1074/jbc.M111.256909
  6. Fredriksson, R., Lagerstrom, M. C., Lundin, L. G. and Schioth, H. B. (2003) The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol. Pharmacol. 63, 1256-1272. https://doi.org/10.1124/mol.63.6.1256
  7. Hilger, D., Masureel, M. and Kobilka, B. K. (2018) Structure and dynamics of GPCR signaling complexes. Nat. Struct. Mol. Biol. 25, 4-12. https://doi.org/10.1038/s41594-017-0011-7
  8. Isberg, V., de Graaf, C., Bortolato, A., Cherezov, V., Katritch, V., Marshall, F. H., Mordalski, S., Pin, J. P., Stevens, R. C., Vriend, G. and Gloriam, D. E. (2015) Generic GPCR residue numbers - aligning topology maps while minding the gaps. Trends Pharmacol. Sci. 36, 22-31. https://doi.org/10.1016/j.tips.2014.11.001
  9. Kawasaki, T., Saka, T., Mine, S., Mizohata, E., Inoue, T., Matsumura, H. and Sato, T. (2015) The N-terminal acidic residue of the cytosolic helix 8 of an odorant receptor is responsible for different response dynamics via G-protein. FEBS Lett. 589, 1136-1142. https://doi.org/10.1016/j.febslet.2015.03.025
  10. Kaye, R. G., Saldanha, J. W., Lu, Z. L. and Hulme, E. C. (2011) Helix 8 of the M1 muscarinic acetylcholine receptor: scanning mutagenesis delineates a G protein recognition site. Mol. Pharmacol. 79, 701-709. https://doi.org/10.1124/mol.110.070177
  11. Kirchberg, K., Kim, T. Y., Moller, M., Skegro, D., Dasara Raju, G., Granzin, J., Buldt, G., Schlesinger, R. and Alexiev, U. (2011) Conformational dynamics of helix 8 in the GPCR rhodopsin controls arrestin activation in the desensitization process. Proc. Natl. Acad. Sci. U.S.A. 108, 18690-18695.
  12. Kleinau, G., Jaeschke, H., Worth, C. L., Mueller, S., Gonzalez, J., Paschke, R. and Krause, G. (2010) Principles and determinants of G-protein coupling by the rhodopsin-like thyrotropin receptor. PLoS ONE 5, e9745. https://doi.org/10.1371/journal.pone.0009745
  13. Kuramasu, A., Sukegawa, J., Sato, T., Sakurai, E., Watanabe, T., Yanagisawa, T. and Yanai, K. (2011) The hydrophobic amino acids in putative helix 8 in carboxy-terminus of histamine H(3) receptor are involved in receptor-G-protein coupling. Cell. Signal. 23, 1843-1849. https://doi.org/10.1016/j.cellsig.2011.06.021
  14. Lan, H., Liu, Y., Bell, M. I., Gurevich, V. V. and Neve, K. A. (2009) A dopamine D2 receptor mutant capable of G protein-mediated signaling but deficient in arrestin binding. Mol. Pharmacol. 75, 113-123. https://doi.org/10.1124/mol.108.050534
  15. Liggett, S. B., Caron, M. G., Lefkowitz, R. J. and Hnatowich, M. (1991) Coupling of a mutated form of the human beta 2-adrenergic receptor to Gi and Gs. Requirement for multiple cytoplasmic domains in the coupling process. J. Biol. Chem. 266, 4816-4821. https://doi.org/10.1016/S0021-9258(19)67722-7
  16. Macey, T. A., Gurevich, V. V. and Neve, K. A. (2004) Preferential interaction between the dopamine D2 receptor and Arrestin2 in neostriatal neurons. Mol. Pharmacol. 66, 1635-1642. https://doi.org/10.1124/mol.104.001495
  17. Markx, D., Schuhholz, J., Abadier, M., Beier, S., Lang, M. and Moepps, B. (2019) Arginine 313 of the putative 8th helix mediates Galphaq/ 14 coupling of human CC chemokine receptors CCR2a and CCR2b. Cell. Signal. 53, 170-183. https://doi.org/10.1016/j.cellsig.2018.10.007
  18. Min, C., Zheng, M., Zhang, X., Caron, M. G. and Kim, K. M. (2013) Novel roles for beta-arrestins in the regulation of pharmacological sequestration to predict agonist-induced desensitization of dopamine D3 receptors. Br. J. Pharmacol. 170, 1112-1129. https://doi.org/10.1111/bph.12357
  19. Missale, C., Nash, S. R., Robinson, S. W., Jaber, M. and Caron, M. G. (1998) Dopamine receptors: from structure to function. Physiol. Rev. 78, 189-225. https://doi.org/10.1152/physrev.1998.78.1.189
  20. Moritz, A. E., Free, R. B. and Sibley, D. R. (2018) Advances and challenges in the search for D2 and D3 dopamine receptor-selective compounds. Cell. Signal. 41, 75-81. https://doi.org/10.1016/j.cellsig.2017.07.003
  21. Namkung, Y., Dipace, C., Javitch, J. A. and Sibley, D. R. (2009) G protein-coupled receptor kinase-mediated phosphorylation regulates post-endocytic trafficking of the D2 dopamine receptor. J. Biol. Chem. 284, 15038-15051. https://doi.org/10.1074/jbc.M900388200
  22. Okuno, T., Ago, H., Terawaki, K., Miyano, M., Shimizu, T. and Yokomizo, T. (2003) Helix 8 of the leukotriene B4 receptor is required for the conformational change to the low affinity state after G-protein activation. J. Biol. Chem. 278, 41500-41509. https://doi.org/10.1074/jbc.M307335200
  23. Pandy-Szekeres, G., Munk, C., Tsonkov, T. M., Mordalski, S., Harpsoe, K., Hauser, A. S., Bojarski, A. J. and Gloriam, D. E. (2018) GPCRdb in 2018: adding GPCR structure models and ligands. Nucleic Acids Res. 46, D440-D446. https://doi.org/10.1093/nar/gkx1109
  24. Rankovic, Z., Brust, T. F. and Bohn, L. M. (2016) Biased agonism: an emerging paradigm in GPCR drug discovery. Bioorg. Med. Chem. Lett. 26, 241-250. https://doi.org/10.1016/j.bmcl.2015.12.024
  25. Rasmussen, S. G., DeVree, B. T., Zou, Y., Kruse, A. C., Chung, K. Y., Kobilka, T. S., Thian, F. S., Chae, P. S., Pardon, E., Calinski, D., Mathiesen, J. M., Shah, S. T., Lyons, J. A., Caffrey, M., Gellman, S. H., Steyaert, J., Skiniotis, G., Weis, W. I., Sunahara, R. K. and Kobilka, B. K. (2011) Crystal structure of the beta2 adrenergic receptor-Gs protein complex. Nature 477, 549-555. https://doi.org/10.1038/nature10361
  26. Santos, R., Ursu, O., Gaulton, A., Bento, A. P., Donadi, R. S., Bologa, C. G., Karlsson, A., Al-Lazikani, B., Hersey, A., Oprea, T. I. and Overington, J. P. (2017) A comprehensive map of molecular drug targets. Nat. Rev. Drug Discov. 16, 19-34. https://doi.org/10.1038/nrd.2016.230
  27. Schonegge, A. M., Gallion, J., Picard, L. P., Wilkins, A. D., Le Gouill, C., Audet, M., Stallaert, W., Lohse, M. J., Kimmel, M., Lichtarge, O. and Bouvier, M. (2017) Evolutionary action and structural basis of the allosteric switch controlling beta2AR functional selectivity. Nat. Commun. 8, 2169. https://doi.org/10.1038/s41467-017-02257-x
  28. Smith, J. S., Lefkowitz, R. J. and Rajagopal, S. (2018) Biased signalling: from simple switches to allosteric microprocessors. Nat. Rev. Drug Discov. 17, 243-260. https://doi.org/10.1038/nrd.2017.229
  29. Sounier, R., Mas, C., Steyaert, J., Laeremans, T., Manglik, A., Huang, W., Kobilka, B. K., Demene, H. and Granier, S. (2015) Propagation of conformational changes during mu-opioid receptor activation. Nature 524, 375-378. https://doi.org/10.1038/nature14680
  30. Weis, W. I. and Kobilka, B. K. (2018) The molecular basis of g proteincoupled receptor activation. Annu. Rev. Biochem. 87, 897-919. https://doi.org/10.1146/annurev-biochem-060614-033910
  31. Westrich, L. and Kuzhikandathil, E. V. (2007) The tolerance property of human D3 dopamine receptor is determined by specific amino acid residues in the second cytoplasmic loop. Biochim. Biophys. Acta 1773, 1747-1758. https://doi.org/10.1016/j.bbamcr.2007.06.007
  32. Zhang, X., Wang, F., Chen, X., Chen, Y. and Ma, L. (2008) Post-endocytic fates of delta-opioid receptor are regulated by GRK2-mediated receptor phosphorylation and distinct beta-arrestin isoforms. J. Neurochem. 106, 781-792. https://doi.org/10.1111/j.1471-4159.2008.05431.x
  33. Zhou, X. E., He, Y., de Waal, P. W., Gao, X., Kang, Y., Van Eps, N., Yin, Y., Pal, K., Goswami, D., White, T. A., Barty, A., Latorraca, N. R., Chapman, H. N., Hubbell, W. L., Dror, R. O., Stevens, R. C., Cherezov, V., Gurevich, V. V., Griffin, P. R., Ernst, O. P., Melcher, K. and Xu, H. E. (2017) Identification of phosphorylation codes for arrestin recruitment by G protein-coupled receptors. Cell 170, 457-469.e13. https://doi.org/10.1016/j.cell.2017.07.002
  34. Zhu, S., Zhang, M., Davis, J. E., Wu, W. H., Surrao, K., Wang, H. and Wu, G. (2015) A single mutation in helix 8 enhances the angiotensin II type 1a receptor transport and signaling. Cell. Signal. 27, 2371-2379. https://doi.org/10.1016/j.cellsig.2015.08.020

Cited by

  1. PAR4 activation involves extracellular loop 3 and transmembrane residue Thr153 vol.136, pp.19, 2020, https://doi.org/10.1182/blood.2019004634
  2. Receptor-Arrestin Interactions: The GPCR Perspective vol.11, pp.2, 2021, https://doi.org/10.3390/biom11020218